Artificial Thymus: Recreating Microenvironmental Cues to Direct T Cell Differentiation and Thymic Regeneration

The thymus supports the development and differentiation of T cells, which are a central component of the mammalian adaptive immune system. From entry of hematopoietic progenitor cells into the thymus to their complex maturation sequence into naive T cells, the role of the thymic microenvironment has been the subject of intense study. A pivotal aspect of this process is the activation of Notch receptors on progenitors by Delta-like (Dll) ligands present on thymic epithelial cells. Thus far, two approaches have been taken to create an artificial thymus, or mimic thymic function. One involves an in vitro cell-based system in which several key components are provided, including Dll and cytokines, to induce and support T cell lineage differentiation. The gold standard approach makes use of a bone marrow-derived cell line (OP9), ectopically expressing Dll (OP9-DL). A related method involves an in vitro cell-free system that provides a similar set of required signaling components. The second approach involves the generation of organized thymic tissue, which can be achieved by direct reprogramming of another cell type or via the differentiation of pluripotent stem cells (PSCs), either by the ectopic expression of the thymic master regulatory gene, FoxN1, in fibroblasts or by inducing the differentiation of PSCs using developmental cues, respectively. These approaches share a similar goal, to generate T cells from different sources of stem cells. However, the former takes advantage of cellular or molecular drivers of T-lineage differentiation, while the latter is focused on creating thymic tissues that would support T cell development.